Triazospiro compounds having nociceptin receptor affinity

Details Triazospiro compounds having nociceptin receptor affinity Triazospiro compounds having nociceptin receptor affinity

2000-12-06

2004-02-03

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S253090, C514S282000, C514S812000, C546S020000, C546S016000, C544S360000

Reexamination Certificate

active

06686370

ABSTRACT:

BACKGROUND OF THE INVENTION
Chronic pain is a major contributor to disability in the industrialized world and is the cause of an untold amount of suffering. The successful treatment of severe and chronic pain is a primary goal of the physician with opioid analgesics being the current drugs of choice. Unfortunately, this class of compounds produces several undesirable side effects including respiratory depression, constipation, and the development of tolerance and dependence.
Opioids are derived from the opium poppy papaya somniferum and include drugs such as morphine, codeine and semi-synthetic compounds derived from them and from thebaine, another component of the opium poppy. It was hypothesized that the opioids derived their therapeutic effect by interacting with specific receptor sites in the body. Later experiments led to the belief that there were more than one receptor site in the body, in explanation for the fact that the synthetic compound nalorphine provides analgesic activity while at the same time, antagonizes the analgesic effect of morphine.
Until recently, there was evidence of three major classes of opioid receptors in the central nervous system (CNS), with each class having subtype receptors. These receptor classes were designated as &mgr;, &dgr; and k. As opiates had a high affinity to these receptors while not being endogenous to the body, research followed in order to identify and isolate the endogenous ligands to these receptors. These ligands were identified as enkephalins, endorphins and dynorphins.
Recent experimentation has led to the identification of a cDNA encoding an opioid receptor-like (ORL1) receptor with a high degree of homology to the known receptor classes. This newly discovered receptor was classified as an opioid receptor based only on structural grounds, as the receptor did not exhibit pharmacological homology. It was initially demonstrated that non-selective ligands having a high affinity for &mgr;, &dgr; and k receptors had low affinity for the ORL1. This characteristic, along with the fact that an endogenous ligand had not yet been discovered, led to the term “orphan receptor”.
Subsequent research led to the isolation and structure of the endogenous ligand of the ORL1 receptor. This ligand is a seventeen amino acid peptide structurally similar to members of the opioid peptide family.
The discovery of the ORL1 receptor presents an opportunity in drug discovery for novel compounds which can be administered for pain management or other syndromes modulated by this receptor.
Given the close structural homology of ligands to the ORL1 receptor to ligands of the other opioid receptors, such drug discovery could also lead to compounds having a higher affinity for the &mgr;, &dgr; and k receptors than known compounds, while producing less side effects.
OBJECTS AND SUMMARY OF THE INVENTION
It is accordingly an object of the present invention to provide new compounds which exhibit affinity for the ORL1 receptor.
It is another object of the present invention to provide new compounds which exhibit affinity for the ORL1 receptor and one or more of the &mgr;, &dgr; or k receptors.
It is another object of the present invention to provide new compounds for treating a patient suffering from chronic or acute pain by administering a compound having affinity for the ORL1 receptor.
It is another object of the invention to provide new compounds which have agonist activity at the &mgr;, &dgr; and k receptors which is greater than compounds currently available e.g. morphine.
It is another object of the invention to provide methods of treating chronic and acute pain by administering compounds which have agonist activity at the &mgr;, &dgr; and k receptors which is greater than compounds currently available.
It is another object of the invention to provide methods of treating chronic and acute pain by administering non-opioid compounds which have agonist activity at the &mgr;, &dgr; and k receptors and which produce less side effects than compounds currently available.
It is another object of the present invention to provide compounds useful as analgesics, antiinflammatories, diuretics, anesthetics and neuroprotective agents and methods for administering said compounds.
It is another object of the invention to provide a method of modulating a response from opioid &mgr; receptors comprising administering a compound having a binding affinity for the &mgr; receptor of less than about 5.0 K
i
(nM), less than about 1.0 K
i
(nM), less than about 0.5 K
i
(nM), less than about 0.1 K
i
(nM) or less than about 0.06 K
i
(nM). In alternate embodiments, the compound has a binding affinity for the ORL1 receptor of less than 100 K
i
(nM), less than about 70 K
i
(nM), less than 20 K
i
(nM), or less than 5.0 K
i
(nM), in addition to, or independently of the &mgr; receptor affinity.
It is another object of the invention to provide a method of reducing side effects associated with the administration of opioid analgesics in a human patient comprising administering to said human patient an analgesically effective amount of a non-opioid compound which exhibits a binding affinity for the &mgr; receptor of less than about 5.0 K
i
(nM), less than about 1.0 K
i
(nM), less than about 0.5 K
i
(nM), less than about 0.1 K
i
(nM) or less than about 0.06 K
i
(nM). In alternate embodiments, the compound has a binding affinity for the ORL1 receptor of less than 100 K
i
(nM), less than about 70 K
i
(nM), less than 20 K
i
(nM), or less than 5.0 K
i
(nM), in addition to, or independently of the &mgr; receptor affinity.
It is another object of the invention to provide a method of reducing side effects associated with the administration of opioid analgesics in a human patient comprising administering to said human patient an analgesically effective amount of a non-opioid compound which exhibits a binding affinity specificity for the &mgr; receptor as compared to the &dgr;
2
receptor (K
i
(nM) at the &dgr;
2
receptor/K
i
(nM) at the &mgr; receptor) of greater than about 10,000, preferably greater than about 12,000 and more preferably greater than about 14,775.
Other objects and advantages of the present invention will become apparent from the following detailed description thereof. With the above and other objects in view, the present invention in certain embodiments comprises compounds having the general formula (I):
wherein
R
2
is selected from the group consisting of hydrogen, C
1-10
alkyl, C
3-12
cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;
Z
1
is selected from the group consisting of a C
1-10
straight or branched alkyl substituted with an oxo or a carbonyl, said carbonyl optionally substituted on the carbon with halogen, C
1-5
alkyl, C
3-5
cycloalkyl, phenyl or phenyl-C
1-3
alkyl; alkenyl or alkenylene, wherein said substituted alkyl, alkenyl or alkenylene is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C
1-10
alkyl, C
1-10
alkyoxy, phenyl, phenyl(C
1-3
)alkyl, said phenyl and phenylalkyl optionally substituted with 1-3 halogen or C
1-10
alkyl;
R
1
is selected from the group consisting of hydrogen, C
3-12
cycloalkyl, C
3-12
cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, and a bicyclic ring system of the formula (II)
wherein A is a saturated, unsaturated or partially unsaturated ring and X
1
and X
2
are independently selected from the group consisting of NH, O, S and CH
2
, wherein said C
3-12
cycloalkyl, C
3-12
cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, and a bicyclic ring system of the formula (II) optionally substituted with 1-3 substituents selected from the group consisting of halogen, C
1-10
alkyl, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 halogen or C
1-10
alkyl; and pharmaceutically acceptable salts thereof.
In certain preferred embodiments the halogen s

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